This laboratory reported the first virus vector-mediated gene transfer into neurons, and we pioneered a helper virus-free Herpes Simplex Virus (HSV-1) plasmid vector system. More recently, we have developed large vectors to coexpress multiple genes, promoters that support long-term expression in forebrain neurons, and modified HSV-1 vector particles for improved gene transfer and expression. Using this vector system, we have begun to explore gene therapy approaches to specific neurological disorders, and we are studying learning. We authored one of the first reports that used direct gene transfer to neurons to correct a rat model of Parkinson's Disease (PD), by expressing tyrosine hydroxylase (TH). Recently, we showed that coexpression of TH, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter-2 supported regulated release of dopamine, high levels of behavioral correction, and long-term expression (~11,000 expressing cells at 6 months). Moreover, we showed that expressing a constitutively active protein kinase C (PKC) in cortical or hippocampal neurons enhanced visual or auditory learning, respectively. In 2 year old rats, expressing this PKC in hippocampal neurons improved spatial learning. Targeted gene transfer to a specific type of neuron is critical for specific gene therapy treatments and neuroscience studies. We targeted gene transfer to nigrostriatal neurons using HSV-1 vector particles that contained chimeric HSV-1 glycoprotein C (gC)-glial cell line-derived neurotrophic factor or gC~brain-derived neurotrophic factor proteins. This study represents the first example of targeted gene transfer to a specific type of neuron in the brain. The goal of this proposal is to systematically develop targeted gene transfer to specific types of neurons, for neural gene therapy and neuroscience. The first specific aim will systematically optimize the parameters that control targeted gene transfer. The second specific aim will develop a general procedure for targeted gene transfer, using antibodies, and develop targeting to specific types of striatal or cortical neurons. The third specific aim will develop a targeting procedure to deliver different genes to paired presynaptic and postsynaptic neurons, that together form a synapse, for studies on synaptic plasticity and learning, and for gene therapy.